9YNX

Local refinement of Fab-14/SARS-CoV-2 D614G spike complex, Mode IV, Subgroup I conformation

9YNX の概要

• エントリーDOI: 10.2210/pdb9ynx/pdb
• EMDBエントリー: 73245
• 分子名称: Spike protein S1, Fab-14 heavy chain, Fab-14 light chain, ... (5 entities in total)
• 機能のキーワード: sars-cov-2, neutraling antibody, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 142913.90

構造登録者

Wang, Y.,Hu, Y.,Leiman, P.,Xie, X. (登録日: 2025-10-12, 公開日: 2026-03-18, 最終更新日: 2026-04-08)

主引用文献

Wang, Y.,Hu, Y.,Ku, Z.,Yeung, J.,Zou, J.,Woodson, M.,Prokhorov, N.S.,Knyazhanskaya, E.S.,Zhao, H.,Sherman, M.B.,An, Z.,Carroll, S.F.,Shi, P.Y.,Leiman, P.G.,Xie, X.
Neutralization of SARS-CoV-2 by IgM-14 via engagement of two distinct spike epitopes.
Plos Pathog., 22:e1014071-e1014071, 2026

PubMed Abstract: Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong resistance. Cryo-electron microscopy analysis uncovered two distinct Fab-RBD interfaces: a primary interface overlapping the angiotensin-converting enzyme 2 (ACE2)-binding region, and a unique secondary interface formed only when the RBD adopts the ACE2-inaccessible "down" conformation, involving a neighboring spike protomer. Site-directed mutagenesis and structural modeling revealed a critical role of this secondary site in IgM-14-mediated neutralization. Unlike IgG-14, structural modeling suggested that IgM-14 can simultaneously engage both interfaces in diverse modes, indicating a noncanonical avidity mechanism. Collectively, these findings highlight the structural and functional uniqueness of IgM-14 and offer valuable insights into the rational design of next-generation spike-targeted antibody therapeutics with enhanced breadth and potency.

PubMed: 41880376
DOI: 10.1371/journal.ppat.1014071

実験手法

ELECTRON MICROSCOPY (4.1 Å)